This invention relates to novel 1,2-dihydropyrido[3,4-b]pyrazines, also known as 1-deaza-7,8-dihydropteridines. This invention also relates to a process for making such compounds and to novel intermediates obtained in said process.
The antimitotic chemical agents commonly known as spindle poisons are plant products of which the best known are colchicine, podophyllotoxin, and the vinca alkaloids. [L. Wilson, J. R. Bamburg, S. B. Mizel, L. M. Grisham and K. M. Creswell, Federation Proceedings, 33, 158 (1974)]. Two members of the latter, vincristine and vinblastine, are currently used clinically in the treatment of neoplasms. Although these agents produce a number of biochemical actions such as the inhibition of macromolecular synthesis, their primary effect is to prevent mitosis by interfering with the function of microtubules, which results in the accumulation of cells in metaphase. In addition, several benzimidazol-2-yl carbamates have been introduced as fungicides, anthelmintics and antitumoral agents. [L. C. Davidse and W. Flach, J. Cell Biol., 72, 174 (1977)]. These compounds also prevent mitosis and their biological activity can probably be attributed to interference with the formation or functioning of microtubules.
The development of procedures for the preparation of 1-deazapteridines is reported by J. A. Montgomery and N. F. Wood, J. Org. Chem., 29, 734 (1964); R. D. Elliott, C. Temple, Jr. and J. A. Montgomery, J. Org. Chem., 33, 533 (1968); R. D. Elliott, C. Temple, Jr., J. L. Frye and J. A. Montgomery, J. Org. Chem., 36, 2818 (1971); and R. D. Elliott, C. Temple, Jr. and J. A. Montgomery, J. Med. Chem., 17, 553 (1974). These references disclose the preparation and use of various 1,2-dihydro[3,4-b]pyrazine derivatives. Thus, the 1964 J. Org. Chem. reference discloses the compounds: ##STR2## The 1968 J. Org. Chem. reference discloses the compound: ##STR3## The 1971 J. Org. Chem. reference discloses the compounds: ##STR4## The J. Med. Chem. reference discloses that a dihydro-1-deazapteridine precursor of 1-deazamethotrexate showed activity against leukemia L1210 in mice. An abstract presented at the 28th Southeast Regional Meeting of the American Chemical Society in Gatlinburg, Tenn., Oct. 27-29, 1976 discloses that the compound ##STR5## showed cytotoxicity in the KB cell culture screen and activity against leukemia L1210 in mice.
An abstract of a paper by B. J. Bowdon, G. P. Wheeler, C. G. Temple and J. A. Montgomery in AACR Abstracts, Vol. 22, March 1981 (page 25) discloses that a compound designated as "NSC-181928" was active against several neoplasms. NSC-181928 is the designation for the compound ##STR6##